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AU676887B2 - Peptide analogs as irreversible interleukin-beta protease inhibitors - Google Patents

Peptide analogs as irreversible interleukin-beta protease inhibitors Download PDF

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Publication number
AU676887B2
AU676887B2 AU60752/94A AU6075294A AU676887B2 AU 676887 B2 AU676887 B2 AU 676887B2 AU 60752/94 A AU60752/94 A AU 60752/94A AU 6075294 A AU6075294 A AU 6075294A AU 676887 B2 AU676887 B2 AU 676887B2
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Australia
Prior art keywords
ketone
aspartic acid
benzyloxycarbonyl
acid
formula
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AU60752/94A
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AU6075294A (en
Inventor
Mark A. Ator
Mohamed M.A. Awad
Prasad V. Chaturvedula
Roland E. Dolle
Denton W. Hoyer
Eric Piatt Lodge
Irennegbe K. Osifo
Catherine P. Prouty
James M. Rinker
Tina Morgan Ross
Joseph M. Salvino
Stanley J. Schmidt
Jasbir Singh
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Vertex Pharmaceuticals Inc
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Sterling Winthrop Inc
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Assigned to SANOFI reassignment SANOFI Alteration of Name(s) of Applicant(s) under S113 Assignors: STERLING WINTHROP INC.
Assigned to VERTEX PHARMACEUTICALS INCORPORATED reassignment VERTEX PHARMACEUTICALS INCORPORATED Alteration of Name(s) in Register under S187 Assignors: SANOFI
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Abstract

Disclosed are compounds, compositions and methods for inhibiting interleukin-1 beta protease activity, the compounds having the formula (I) <CHEM> wherein R1 is an acyl group, as defined herein, A is an amino acid group as defined herein, n is 0-4 and Y is <CHEM>

Description

AUSTRALIA
Patents Act COMPLETE SPECIFICATION
(ORIGINAL)
Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: S Name of Applicant: Sterling Winthrop Inc.
Actual Inventor(s): James M. Rinker Eric Piatt Lodge Denton W. Hoyer Roland E. Dolle Irennegbe K. Osifo Stanley J. Schmidt Tina Morgan Ross Prasad V. Chaturvedula Catherine P. Prouty Mohamed M. A. Awad Joseph M. Salvino Jasbir Singh Mark A. Ator Address for Service: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: PEPTIDE ANALOGS AS IRREVERSIBLE INTERLEUKIN-BETA PROTEASE
INHIBITORS
Our Ref 363262 POF Code: 4703/154162 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1i -i1 EKDN 62040 PEPTIDE ANALOGS AS IRREVERSIBLE INTERLEUKIN-1 PROTEASE INHIBITORS BACKGROUND OF THE INVENTION Field of the Invention This invention relates to peptide analogs that are interleukin-1 B protease inhibitors. More particularly, the invention provides a-substituted methyl ketones derived from :aspartic acid and the closed hemi-ketal forms thereof as 15 inhibitors of interleukin 1-p protease.
*ee Reported Developments Enzymes involved in the catalytic degradation of proteins by hydrolyzing peptide bonds are known as proteases or protelnases.
:0 Proteinases are believed to be involved in various disease states including inflammation, metastasis, tissue damage, bone resorption and muscle degeneration in dystrophic diseases.
Proteinases are divided into classes according to their catalytic 25 mechanisms, such as serine-, cystein-, aspartic- and metalloproteinases. For each class of proteinases, the catalytic site of the enzyme lies in the cleft on the surface of the enzymes in S. which reside the specificity subsites that bind amino acid side chains and the polypeptide backbone. In designing proteinase inhibitors, it is important to optimize the subsite binding characteristics with appropriate amino acid substrate analogs.
This invention relates to peptide substrates modified with affinity labels that inhibit interleukin-1 protease (hereinafter IL-1p protease). These inhibitors are thought to act by alkylating the cysteine sulfhydryl group (cys 285) within the catalytic site of IL-1p protease. Affinity labeling has been used since the 1960's to prepare irreversible peptide-based inhibitors which act S-2- EKDN 62040 to alkylate the active sites of cysteine proteases. A variety of affinity labels and amino acid sequences have been synthesized to improve the binding of these modified peptide inhibitors to the enzyme's active site. These affinity labels include peptidyl halomethyl ketones, peptidyl diazomethyl ketones, epoxysuccinyl peptides and peptidyl methylsulphonium salts as reviewed by D.
Rich in Chapter 4 of "Proteinase Inhibitors", Barret, A.J. and Salvesen, eds,, Elsevier, 1986. More recently, peptide acyloxymethyl and aryloxymethyl ketons have also been described as affinity lables (Krantz, A. et al, Biochemisty, 30, p. 4678- 4687, 1991). Current research (see for example European Patent Application, Pub. No, 015,748 A2; PCT International Publication No, WO 91/15577; Chapman, Biorganic Medicinal Chem.
Lett. 1992, 2, 613-618) has been directed towards understanding 15 the enzyme binding specificity requirements in designing novel small molecular weight protease inhibitors that are efficacious, safe and have specificity for IL-1p protease which is believed to play an important role in many disease states (see Epstein, F.H., New Engl. Jrl. of Med., 2S., p. 106-113, 1993).
Disease states in which IL-1p protease inhibitors may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; $too' inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain tumors.
It is an object of the present invention to provide novel peptidyl substrate analogs modified with electronegative leaving groups that bind at the active site of IL-1p protease and inhibit IL-1p protease activity. IL-1p protease cleaves a biologically inactive 34kD precursor of IL-1 to form the biologically active 17kD cytokine. This cleavage occurs at the peptidyl sequence of Val-His-Asp/-Ala-Pro-Val.
EKDN 62040 It is another object of the present invention to provide compositions comprising the above-referred to compounds.
It is a further object of the present invention to provide a method of use of the composition for the treatment of the aboveidentified disease states.
SUMMARY OF THE INVENTION According to the present invention, there is provided a compound of the formula and a pharmaceutically acceptable salt thereof:
H
A -NA-Y n Formula I wherein n 0-4; 0* a a 0
H
H R2
R
4 CH 2 O(CO)mR 3 0 0
H
or R4- CHZ0(CO)mR 3
OH
Ca
O
m 0,1;
R
3 a singularly or multiply substituted aryl wherein aryl is a phenyl or naphthyl ring wherein the substituents are independently selected from the group consisting of:
H
halogen
CM
CF3 EKDN 62040 N02 COR9
NR
6 0OR10 CONR5R6 SO2NR5R6 (11) S021R 6 (12) COOR11 (13) -O-(CH 2 1 6 r and -0ORI, (14) lower alkyl and lower cycloalkyl lower straight chain or branched alkyl, lower cycloalkyl (CRGR7)0.6-aryl t,3Q) (CRGR7)o.6-heteroaryl or (0R6R7)2-6-R8;
R
6 and R7 are independently H, lower straight chain or branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined as above and heteroaryl Includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, qulnolyl, isoquinolyl, isothiazolyl, benzofuranyl, s triazinyl and tetrazolyf; R8 OCH2CH2OR6 OCH2CH2NR6R7 NR6CH2CO2R6 30(5) or N x X -OQ and
NH
6 R17 wherein R6 and R7 are as above deflned; EKDN 62040 Rg= cycloalkyl lower straight chain or branched alkyl, lower (CReR7)o..B-aryl; (CR6R7)o.6-heteroaryl; or
(CR
6
R
7 )0.6-R 8 wherein R6, R7 and RB ',1zr, as defined; above Rjo (1) (2) (3)
OR
1 1
NR
6 Rjj, 0 0* 0 0* *505 S S wherein R1cycloalkyl lower straight chain or branched alkyl, lower (CR6R 7 1 .6-aryl;
(CR
6 R7)i 6 -heteroaryl;, (0CR6R 7 2 .B-R8, and R 6 or
R
7 and R 8 are as above d e firi ed; R4 H or deuterium-,
R
2 1 (3) OR6
NR
6 OR7 or
NR
6
R
7 and R6 and R 7 are as above-defined; *5 SO S 5.
5* S5 S5 A an amino acid of the formula (11) R6 0
R
7
R
1 2 Formula (ii) wherein R6 and R7 are as defined above; R12 Is Independently H or wm
I
EKDN 62040 (0R 6 R7)1.6-RI3, and R6 and R7 are as abovedefined;
S
S.
S
R
1 3 H
F
0F3
CH
ORii1
NR
6 Rj 4 cycloalkyl aryl heteroaryf (10)
SH
(11) SRii1 (12) CONR 5
R
6 (13) COOR 5 or (14) ,-Oj R14- R 7 OCOR1 0 SO2NR5R6 or S S *5 S S
SS
6 ANR6R, or A (2) consisting of an amino acid selected from the group 0 EKDN 62040 (2)
S
es (8) 1 0
H
and aN (12)
I,
4* C C R1 Is an acyl group of the formula (111) Formula IIl w he rein R12 IS QRs NR5R6 Rs EKIDN 62040
R
5 (6)
R
5
RN-(CH
2 1 4 R6 (7 N R s o CCC. (8) wherein R 15 single bond, (CH 2 2 .6-NR 6
(CH
2 2 6 and
R
6 are as above defined; or a sulfonyl group of the formula (IV) CS C 0 R1 IS 0.
8a wherein r) and R 6 are as above-defined.
Throughout the description and claims of the specification the word "comprise" and variations of the word, such as "comprising" and "comprises" is not intended to exclude other additives, components, integers or steps.
off so4 o **s a 0 0 06000: 4 *4 C WHNWoRDJUUiEPECieswiO.S294DO S-9- EKDN 62040 wherein:s fRV-l.,, *rflpr i o v nu.
As used herein the term pharmaceutically acceptable salts include the acid and base addition salts.
The term acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, 15 ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
ease The term base addition salts include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, 20 calcium, magnesium, iron, zinc, copper, manganese, aluminum Ssalts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, S" trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaines, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine.
I-
EKDN 62040 "Alkyl" means a saturated or unsaturated aliphatic hydrocarbon which may be either straight- or branched-chain.
Preferred groups have no more than about 12 carbon atoms and may be methyl, ethyl and structural isomers of propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
"Lower alkyl" means an alkyl group as above, having 1 to 7 carbon atoms. Suitable lower alkyl groups are methyl, ethyl, npropyl, isopropyl, butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, and n-heptyl.
"Substituted phenyl" means a phenyl group in which one or more of the hydrogens has been replaced by the the same or different substituents including halo, lower alkyl, nitro, amino, 15 acylamino, hydroxyl, lower alkoxy, aryl, heteroaryl, lower alkoxy, alkylsulfonyl, trifluoromethyl, morpholinoethoxy, morpholinosulfonyl, and carbobenzoxy-methyl sulfamoyl.
"Halogen" means chloride, fluoride, bromide or iodide.
"Lower cycloalkyl" means cycloalkyl having C 3 to C 6 carbon atoms.
The present invention also concerns the pharmaceutical composition and method of treatment of IL-1P mediated disease states or disorders in a mammal in need of such treatment comprising the administration of IL-113 inhibitors of formula (I) as the active agent. These disease states and disorders include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, immune-based diseass, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain tumors.
I I -11- EKDN 62040 In the practice of this invention an effective amount of a compound of the invention or a pharmaceutical composition thereof is administered to the subject in need of or desiring, such treatment. These compounds or compositions may be administered by any of a variety of routes depending upon the specific end use, including orally, parenterally (including subcutaneous, intraarticular, intramuscular and intravenous administration), rectally, buccally (including sublingually), transdermally or intranasally. The most suitable route in any io given case will depend upon the use, the particular active ingredient, and the subject involved. The compound or composition may also be administered by means of controlledrelease, depot implant or injectable formulations as described more fully herein.
In general, for the uses as described in the instant invention, it is expedient to administer the active ingredient in amounts between about 0.1 and 100 mg/kg body weight, most preferably from about 0.1 to 30 gig/kg body weight for human 20 therapy, the active ingredient will be administered preferably in the range of from about 0.1 to about 20-50 gg/kg/day. This administration may be accomplished by a single administration, by distribution over several applications or by slow release in order to achieve the most effective results. When administered 25 as a single dose, administration will most preferably be in the range of from about 0.1 to 10 mg/kg of body weight The exact dose and regimen for administration of these compounds and compositions will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment, and the degree of affliction or need. In general, parenteral administration requires lower dosage than other methods of administration which are more dependent upon absorption.
I -12- EKDN 62040 A further aspect of the present invention relates to pharmaceutical compositions comprising as an active ingredient a compound of the present invention in admixture with a pharmaceutically acceptable, non-toxic carrier. As mentioned above, such compositions may be prepared for use for parenteral (subcutaneous, intraarticular, intramuscular or intravenous) administration, particularly in the form of liquid solutions or suspensions; for oral or buccal administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops or aerosols.
When administered orally (or rectally) the compounds will usually be formulated into a unit dosage form such as a tablet i capsule, suppository or cachet. Such formulations typically 15 include a solid, semi-solid or liquid carrier or diluent. Exemplary diluents and vehicles are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, mineral oil, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, syrup, methylcellulose, polyoxyethylene sorbitar monolaurate, 20 methyl hydroxybenzoate, propyl hydroxybenzoate, talc, and magnesium stearate.
The compositions may be prepared by any of the methods well-known in the pharmaceutical art, for example as described 25 in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985. Formulations for parenteral administration may contain as common excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
Examples of vehicles for parenteral administration include water, aqueous vehicles such as saline, Ringer's solution, dextrose solution, and Hank's solution and nonaqueous vehicles such as fixed oils (such as corn, cottonseed, peanut, and sesame), ethyl oleate, and isopropyl myristate. Sterile saline is a preferred vehicle and the compounds are sufficiently water soluble to be I I a -13- EKDN 62040 made up as a solution for all foreseeable needs. The vehicle may contain minor amounts of additives such as substances that enhance solubility, isotonicity, and chemical stability, e.g., antioxidants, buffers, and preservatives. For oral administration, the formula can be enhanced by the addition of bile salts and also by the addition of acylcarnitines (Am. J. Phvsiol. 251:332 (1986)).
Formulations for nasal administration may be solid and contain as exciplents, for example, lactose or dextran, or may be aqueous or oily solutions for administration in the form of nasal drops or metered spray. For buccal administration typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
When formulated for nasal administration the absorption 15 across the nasal mucous membrane is enhanced by surfactant acids, such as for example, glycocholic acid, cholic acid, taurocholic acid, desoxycholic acid, chenodesoxycholic acid, dehydrocholic acid, glycodeoxy-cholic acid, and the like 'ee, B.H.
Vickery, "LHRH and its Analogs-Contraception and Theai~'peutic Applications", Pt. 2, B.H. Vickery and J.S. Nester, Eds., i' Press, Lancaster, UK, 1987).
0 -14- EKDN 6~2040 DETAILED DESCRIPTION4 OF THE INVENTION Compounds of the present invnetion are prepared using the procedure described generally in Schemes 1, 11 and Ill and in more detail described in the Examples.
Scheme I a
A.
*9 A. A
A
a
A*
A A COOt-Bu Z-(A)m.HN, COCH Formula A (Z=PhCH 2 =0) Ethyl chioroformate (11) diazomethaneCOtB(v)iH(oR 3
)H
(Ml) HBr-HOAc and-B KF)IH(o 31O Z(A)m-HN fCOH 2 Br adK Formula B COot-BU Z-(A)m-HN CCHAOCO)V Trifluoroacetlc
COOH
acid Z.(A)m'HN COCH 2 O(CO)nR 3 Formula C 0, 1) 0 Z.(A)m-IN4HO C(C)nR 3 Formula 1A Formula 1 (ne. 0,1)
A.
a A
A.
A. A
AA
S.
wherein A, R 3 and m are as defined in formula and Z is benzyloxycarbonyl.
EKDN 62040 COOt-Bu Z-(A)m-HN fCOCH 2 0(CO)nR 3 H, ;Pd/C Formula C 0, 1); (m.Ou Formula D (11) FRCOCI or jXOC N-methyl morpholine COOt-Bu Rjp(A)m-HNf,
COCH
2 0(CO)nR 3 (111) Trifluoroacet-' acid 0b 0* 6 0S *666 Formula E
COOH
Rli(A)m-HN COCH 2 0(CO)nR 0 0
R
1 (A)mHNj (Cn3 HO OC)R Formula 2A Formula 2 666 66 6@ 6 wherein Z, A, R1, R 3 m and n are as defined in formula Scheme II 66 6* 6 Chiorosulfonic a c Id C0 2
H
2C 6 NI cIN%& 2 NRSR6 Formula 3 Formula F Forla FFormula G -16- EKDN 62040 Methods of Preparation The synthesis of the disclosed interleukin enzyme (ICE) inhibitors was conducted by one of two methods depicted in Schemes I and II. For inhibitors which contained an N-terminal benzyloxycarbonyl group group), N-benzyloxycarbonyl-Laspartic acid mon t-butyl ester or other benzyloxycarbonyl protected aspartic acid-based peptides (Formula A) were used as starting materials. The synthesis of the requisite peptides are o1 readily carried out by a variety of methods known to those practicing in the art of peptide chemistry. The aspartic acidbased peptide (Formula A) is reacted with ethyl chloroformate and N-methyl morpholine in tetrahydrofuran (THF) at low temperature (ca. -15 0 C) for approximately 30 min. This generates 0400 15 a mixed anhydride in solution thereby activating the free carboxylate toward nucleophilic attack. Other activating reagents Isopropyl chloroformate), solvents (diethyl ether, dioxane), and tertiary amine bases (diisopropvl ethyl amine, triethyl amine) can be used in place of the above preferred 20 reagents to form a reactive carboxylate species. The pre-formed mixed anhydride is treated (without isolation) with a solution of diazomethane in diethyl ether. The diazomethane reagent is prepared under standard conditions from DIAZALD® using a commercially available (Aldrich) diazomethane -enerator, A one to two molar excess of diazomethane is added and the reaction mixture is warmed from -150C to 25 0 C over a 20 min period.
During this time, diazomethane reacts with the mixed anhydride to form an a-dlazoketone. The a-diazoketone is not isolated by the reaction mixture is treated directly with an excess of a 1:1 solution of 48% hydrobromic (HBr) and glacial acetic (HOAc) acids. 'The mixture of acids are added dropwise to the adiazoketone and the reaction mixture is subsequently stirred for at least 15 minutes. This treatment with 1:1 48% HBr and glacial HOAc decomposes the a-diazoketone to yield the desired Nbenzyloxycarbonyl-L-aspartic acid mono t-butyl ester abromoketone (Formula B) and nitrogen gas as a by-product. The -17- EKDN 62040 bromomethyl ketone is typically isolated as an oil using standard procedures which are apparent to those skilled in the art. The abromoketone so obtained is of sufficient purity to be used in all subsequent reactions. However, the ketone can be further purified by high pressure liquid chromatography (HPLC), if analytically pure material is desired.
The t-butyl ester a-bromoketone (Formula B) is subsequently reacted with a variety of phenols, naphthols, and o1 arylcarboxylic acids. This is conducted by exposing the bromomethyl ketone to an excess of the phenol or arylcarboxylic acid in dimethylformamide containing sodium or potassium a nydride or potassium fluoride, The reaction can be conveniently monitored by thin layer chromatography (TLC) and once the TLC 15 indicates that displacement of the bromide with the phenol or carboxylate is completed, the product Is isolated using standard procedures. The desired aspartic acid mono t-butyl ester as aryloxymethyl- or a-arylacyloxymethyl ketone (Formula C) may be purified by conventional methods including recrystallization and silica gel column chromatography.
06 0. The remaining synthetic transformation to generate the ICE Inhibitors is the hydrolysis of the t-butyl ester function. This is conducted by exposing the t-butyl ester (Formula C) to a 25 solution of trifluoroacetic acid (TFA) in methylene chloride at 250C. The de-esterification is typically complete within 3 hrs.
Removal of the volatile TFA and organic solvent affords the aspartic acid (Formula The yield of the reaction is quantitative in most instances, providing the t-butyl ester starting material is of high purity. Purification, if required, can be performed by recrystallization or chromatographic techniques which are well known to those skilled in the art. The concentration of TFA may range from 5%-100% and other organic solvents may be used such as chloroform, Alternatively, a solution of three molar anhydrous hydrochloric acid in einyl acetate may be used in place of the TFA-methylene chloride -18- EKDN 62040 solution with equal efficiency, L, -H NMR spectra of these acids of Formula 1 indicate that they exist in equilibrium as the closed hemiketal form shown in Formula 1A and that the ratio of Fomula 1 versus Formula 1A is solvent dependent.
In Scheme II, the synthesis of aryloxy- and arylacyloxymethyl ketones (Formula 2) which possess an Nterminal group other than the Z-group are described. The aspartic acid derivatives of Formula C are the starting material for the synthesis of inhibitors of Formula 2. First the Z-group is removed to generate the N-terminal amine (Formula D) under hydrogenoiytic conditions, The reagents and conditions typically used to carry out the hydtogenolytic removal of the Z-group are hydrogen gas, ambient temperature conditions and pressure, 15 palladium on carbon as the catalyst in an alcoholic solvent e.g., methanol, optionally containing two equivalents of hydrochloric acid, It is not necessary to purify the intermediate free amine (or the hydrochloride salt if hydrochloric acid is used in the hydrogenolysis), though this material needs to be dry and free of alcohol for the subsequent coupling reaction to proceed in good yield, The N-terminal amine is then condensed with a carboxylic acid to yield intermediates of Formula E. It Is generally S. 25 necessary to first activate the acid as an acid chloride or mixed anhydride and then react It with the free amine (or hydrolchloride salt) in the presence of an organic base, N-methylmorpholine.
Alternatively, coupling with acid with the intermediate amine is conducted using amide coupling reagents/conditions employed in peptide coupling chemistry ("The Practice of Peptide Synthesis", M. Bodanszky, Springer-Verlag, NY, 1984; "The Peptides", Vol 1-3, E. Gross and J, Melenhofer, Eds. Academic Press, NY, 1981), Lastly, the t-butyl ester in Formula E is removed with trifluoroacetic acid (as described above) to give the aspartic acid analogs of Formula 2. As in the case of the compounds of Formula 1, the 1 H NMR of components of Formula 2 appear to exist in -19- EKDN 62040 equilibrium with their corresponding closed hemiketal counterparts of Formula 2A.
The phenols, naphthyls and arylcarboxylic acids used in the reaction with the bromomethyl ketones can be either purchased form commercial sources or synthesized by adopting known procedures. Their synthesis would be readily deduced by those skilled in the art of organic synthesis. By way of example, the preparation of the 2,6-dichloro-3-sulfonamido benzoic acids a-e to presented in Scheme III. Tlius, 2,6-dichlorobenzoic acid (Formula F; available from Aldrich Chemical Co.) is reacted with chlorosulfonic acid to yield the intermediate sulfonyl chloride (Formula The electrophilic sulfonyl chloride is reacted with a SC;. variety of amines to give the substituted benzoic acids (Formula 15 3).
Intermediate compounds for use in making the final compounds of the present invontion are desc:ibed in Examples 1 37.
Example.
2N-Benzyloxvycarbonv-L-Laspartic acid bromomethv etfft ert-butyl ester To a solution of N-benzyloxycarbonyl L-aspartate p-tertbutyl ester (Formula A; 10 g, 31 mmol) 70 ml of anhydrous THF at -15 0 C was added N-methyl morpholine (4.7 ml, 43,4 mmol) followed by the dropwise addition of ethyl chloroformate (3.9 ml, 40.5 mmol). The reaction mixture was stirred for 30 min at and the suspension treated with diazomethane in ether (160 ml of a 0.4 in solution In ether, prepared from "DIAZALD®" [Aldrich]) and warmed to room temperature.
The bromomethyl ketone was formed in the same pot by cooling the intermediate diazoketone above followed by the EKDN 62040 dropwise aduition of a 1:1 solution of 48% hydrioorornic acc' and glacial acetic a--ld (62 ml), After stirring for 15 min the reaction mixture was poured into a separatory funnel. The aqueous layer was drawn off and discardec,,, The remaining organic phase was washed with water, saturated aqueous NaHCO3, brine and dried (MgSO4). The solvents were removed in vacuo and the title compound so obtained 41-43 0 C) was used in the subsequent displacement reactions without further purlifiCatlon.
d IchJo robe 0z yloxnjgbjW N-Benzyloxycarbonyl-L-aspartic acid oi'omomethvl ketone P-tori-butyl ester (0.30 g; 0.76 rnM) was dissolved 1, 12 ml of anhydrous DMF. To this solution was added powdered potassium (0.11 g; 19 mmol) and 2,5-6'chlorobenzolc acid (0.17 g; 0.091 mmol) and the reaction mixture was stirred overnight. The solution was diluted with Et2O and washed with water, aqu6eous saturated NaHCO3, brine and dried (MWON). The ketone so obtained was purified by silica qel chromatography using ethyl acetate/hexane as the eluting solvent (11- NMR (CDCI3) 8 7,35 (in, a 25 5.90 2H each), 5.20 (mn, 4H), 4,70 (in, 1H), 3.00 and 2.75 a. to (doublet of doublets, 1 H each), 1.42 (in, 9H).
In a similar manner, the following compounds of formula B were prepared: pL N-Benzyloxycarbonyl-L-aspartic acid 2,6difluorophenoxy-inethyl ketone f-tert-butyl ester from N-benzyloxycarbonyl-L.-aspartic acid broinomethyl ketone f-tert-butyl ester and 2,6-difluorophenol (mp 50-5100').
-21- -21- EKDN 62040 Exmple 4 N-Benzyloxycarbonyl-L-aspartic acid 2,6ditrifluoromethyl benzyloxymethyl ketone j3-tert-b utyl ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyl ketone J-tert-butyl ester and 2,6ditrifluoromethyl benzoic acid (mp 62-63OC).
Ex mpJe Ben zyloxycarbo nyl-L-aspartic acid 2,6dichiorophenoxymethyl ketone f-tert-butyl ester from seesN-benzyloxycarbonyl-L-aspartic acid bronornethyl 15ketone P-tert-butyl ester and 2,6-dichioro-phenol.
"4-Benzyloxycarbonyl-L-aspartic acid 2-fluoro-4-(N.
morpholinyl sulfonamido)phenoxymethyl ketone f3-tertbutyl ester from N-benzyloxycarbonyl-L-aspartlc acid bromomethyl ketone f3-tert-butyl ester and 2-fluoro-4- (Nl*-morph olin yl s ulfor imldo) phenol.
Ex am2le 7 N-Benzyloxycarbonyl-L-aspartic acid 2-chloro-4-(Nthiomorphollnylsulfonamido)phenoxymethyI ketone 13tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyl ketone 1-tert-butyl ester and 2chloro-4-(N-tlliomorpholinyl sulfonamido) phenol, N-Benzyloxycarbonyl-L-aspartic acid 2,8-dichloro-3- (2-N-morpholinylethoxy)benzoyloxymethyI ketone P3- EKDN 62040 tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyl ketone f-tert-butyl ester and 2,6dichloro-3-(2-N-morpholinylethoxy) benzoic acid.
xme2 N-Benzyloxycarbonyl-L-aspartic acid 2,6-dimethoxy benzoyloxymethyl ketone P-tert-butyl ester from Nbenzyloxycarbonyl-L-aspartic acid bromomethyl ketone P.tert-butyl ester and 2,6-dimethoxy-benzoic acid.
Ex*l JQ *-ezlxcronlLapri acd26dihco3 (bezyloxy benzoloxmthlkeoe -er-utlese N-Benzyloxycarbonyl-L-aspartic acid 2-lchkamro-3- (benzoxy ben zoyloxym ethyl ketone f3-tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyl ketonie f-tert-butyl ester and 2-dichlordo-3- (benolobenzoic acid acid 2-aeado6 cioro benzoyloxy-methyl ketone tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyl 5ketonie 1-tert-butyl ester and 2-acdaio-6-cacd .23- EKDN 62040 Example 13, N-Benzyloxycarbonyl-L-aspartic acid 3-(Nbutylsulfonamido)-2,6- dichlorobenzoyloxymethyl ketone 1-tert-butyl ester from N-benzyloxycarbonyl-Laspartic acid bromomethyl ketone f-tert-butyl ester and 3-(N-butylsulfonamido)-2,6-dichorobelzoic acid.
Examplle 14 N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3- .6 .:0sulfonamido benzoyioxymethyl ketone P-tert-butyl :00000ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyl ketone j3-tert-butyl ester and 2,6- 15 dichloro-3-sulfonamidobenzoic acid.
20 N-Benzyloxycarbonyl-L-aspartic acid-3-(N- 0: benzylsulfonamido)- 2,6-dichlorobenzoyloxymethyl ketone J-tert-butyl ester from N-benzyloxycarbon),l-Laspartic acid bromomethyl ketone f-tert-butyl ester and 3-(N-benzylsulfonamido)benzoic acid.
N-Benzyloxycarbonyl-L-aspartio acid aminoacetamidoyl] sul;-7namido)-2,6dichlorobenzoyloxymethyl ketone P-tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyt ketone 1-tert-butyl ester and aminoeicetamidoyIJ sulfonamido)-2,6-dichlorobenzoic acid.
-24- EKDN 62040 Example 17 N-Benzyloxycarbonyl-L-aspartic acid 2,6-dich loro-3- (N-morpholinylsulfonamido)benzoyloxymethyl ketone tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid bromomethyl ketone 1-tert-butyl ester and 2,6dichloro-3-N-morpholinyl sulfonamido)benzoic acid.
Example 18 N-Methoxycarbonyl-L-Afanine-L-Aspartic, Acid 2.6-dichlorobenzoyloxmethbYl Ketone 1-tert-Butyl Ester and other Compoujnds, of Formulal E P~art N-benzyloxycarbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone 1-tert-butyl ester (1.02 g, 2 mmol) was dissolved in absolute ethanol (100 ml) containing 6 N ::..aqueous HOI (0.67 ml, 4 mmol). 10% Palladium on carbon (96 mg) was added and the reaction mixture was stirred under an ambient atmosphere of hydrogen gas for approximately 1 hour (thin layer chromotography MeOH-CH 2 CI2] indicated the disappearance of *starting material). The solution was filtered and the solvent was removed in vacuo to give L-aspartic acid 2,6- .dichlorobenizoyloxymethyl ketone 1-tert butyl ester-HCI salt 25 (Formula D) which was used immediately in the subsequent reaction described in Part B.
Part Bl: A solution of N-methoxycarbonyl-L-alanine (301 mg, 2.05 mmol) in CH2CI2 (10 ml) was cooled to -20 0 C and isobutylchloroformate (0.28 ml, 2.05 mmol) and Nmethylmorpho line (0.23 ml, 2.05 mmol) were added sequentially, The reaction mixture was stirred for 15 minutes and a solution of aspartic acid 2,6-dichlorobenzoyl methyl ketone 3- tert-b uty I ester-HCI salt (prepared In Part A above) followed by a second addition of N-methyl morpholine (0.23 ml, 2.05 mmol).
I
EKDN 62040 The reaction mixture was stirred for 30 minutes and was then diluted with EtOAc, washed with water, aqueous saturated NaHCO 3 brine and dried (MgSO 4 The solvents were removed in vacuo and the product purified by silica gel chromatography using 40% EtOAc--hexane as eluent to give N-methoxycarboryl-Lalanine-L-aspartic acid 2,6-dichlorobenzoyl methyl ketone P-tert ester (0.72 g; In a similar fashion the following compounds of Formula E io were prepared: N-(2-Thienyl)carbonyl-L-aspartic acid 2,6dichlorobenzoyloxy- methyl ketone P-tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid 2,6dichlcarobenzoyloxymethyl ketone f-tert-butyl ester and 2-thiophene carboxylic acid.
Example N-Methoxycarbonyl glycine-L-aspartic acid 2,6dich lo robe nzoyloxy- methyl ketone P-tert-butyl ester N-benzyloxycarbonyl-L-aspartic acid 2,6- 25dichlorobenzoyloxymethyl ketone P-tert-butyl ester and N-methoxycarbonyl glycine, Example 21 N-Methoxycarbonyl-L-phenylalanine-L-aspartlc acid 2,6dichloro- benzoyloxymethyl ketone f-tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone j3-tert-butyl ester and N-methoxycarbonyl-L-phenyl alanine.
-26- EKDN 62040 Exmple 22 N-Methoxycarbonyl L-f-(2-thienyl)alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyI ketone P-tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone P-tert-butyl ester and N-methoxycarbonyl-L-]3-(2-thienyl)alaine.
',1-MethoxycarbonyI-L-valine-L-aspartic acid 2,6- .dichlorobenzoyl-oxymethyl ketone P- tert-butyl ester :::from N-be-nzyloxycarbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone P-tert-butyl ester and N-methoxycarbonyl-L-valine.
Example 24 N-Methoxycarbonyl-L-histldine-L-aspartic acid 2,6d ic h Ioro -b en zo ylIo xym e thylI ketone JP-tert-butyl ester from N-benzyloxy-carbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone fP-tert-butyI ester and *NN-methoxycarbonyl-L-histidine.
25 Eape2 N- Benzyloxycarbo nyl- L-alIanIn e- L-aspartic acid 2,6dichloro-benzoyloxymethyl ketone j3-tert-butyl ester from N-benzyloxy-carbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone f-tert-butyl ester and N-benzyloxycarbonyl-L-valine.
ExaMple26.
N-Benzyloxycarbc'nyl-L-alanine-L-aspartic acid 2,6dichloro-benzoyloxymethyl ketone f3-tert-butyl ester from N-benzyloxy-carbonyl-L-aspartic acid 2,6- -27- EKDN 62040 dichlorobenzoyloxymethyl ketone 1-tert-butyl ester and N-benzyloxycarbonyl-L-alanine.
Example 27 i) Benzyloxycarbonyl-L-valine-L-alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone p-tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone P- tert-butyl ester and N-benzyloxycarbonyl-L-valine-L-alanine.
~mi 28 N--uu*LAori Acd2*Dcho9ezvlx~t 15 .*tn -et-uv se LL~.Fur6vl--Aspartic cd 2.6-Dichlorobenzcvaoidmethy dichlorobenzoyloxymethyl ketone f-tert-butyl ester (1.02 g, 2 mmoi) was dissolved in absolute ethanol (100 ml) containing 6 N aqueous HCI (0.67 ml, 4 mmol). 10% Palladium on carbon (96 mg) was added and the reaction mixture was stirred under an ambient atmosphere of hydrogen gas for approximately 1 hour (thin layer see* chromotography [15% MeOH--CH 2 CI2] indicated the disappearance :0of starting material). The solution was filtered and the solvent :25 was removed in vacuo to give L-aspartic acid 2,6- *d dch lo robe nzoyloxymethyl ketone r-tert-ester-HCI salt (Formula D) which was used immediately in the subsequent reaction described in Part B.
aat--: To a solution of L-aspartic acid 2,6dichlo robe nzoyloxy meth yl ketone P-tert-butyl ester-HCI salt mmol, prepared in Part A above) in 0H2C1 2 (10 ml) at 0OC was added 2-furoyl chloride (0,21 ml, 2.05 mmol). Nmethylmo rpho line (0.25 ml; 2.10 mmol) was then added and the reaction mixture stirred for 1 hour as it slowly was allowed to warm to room temperature. The solution was diluted with EtOAc, washed with water, saturated aqueous NaHCO 3 brine and dried -28- EKDN 62040 (Mg SO 4 The solvents were removed in vacuo. The product was purified by silica gel chromatography using 30% EtOAc-hexane as eluent to give N-2-furoyl-L-aspartic acid 2,6d ich lorobe nzoyloxymethyl ketone f3-tert-butyl ester (mp 73- 7400).
In a similar fashion the following compounds of Formula E were prepared- N-2-Furonylcarbonyl-L-aspartic acid 2,6-dichloro-3-(Nmorpholinylsulfonamido) benzoyloxymethyl ketone f3tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(N-morpholinylsulfonamido) benzoyloxymethyl ketone f-tert-butyl ester and 2-furoic acid chloride.
Phenylpropionyl)-L-aspartic acid 2,6d ich lo robe nzoyloxy- methyl ketone J-tert-butyl ester from N-benzyloxycarbonyl-L-aspartic acid 2,6dlchlorobenzoyloxymethyl ketone j3-tert-butyl ester and 21 3-phenylpropionyl chloride.
N- Methoxycarbo ny l-L-aspa rtic acid 2,6dichlorobenzoyloxymethyl ketone A-tert-butyl ester from N-benzyloxycarbo nyl-L-aspa rtic acid 2,6dichlorobenzoyloxymethyl ketone j3-tert-butyl ester and methyl chloroformate.
-29- EKDN 62040 Example 3a N-(N,N-4-Dimethylaminomethyl)benzoyl-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone p-tert-butyl ester 63-65 0 C) from 2,6-dichlorobenzoyloxymethyl ketone p-tert-butyl ester and 4-(N,Ndimethylaminomethyl)benzoyl chloride.
Example 33 3- N-ButvLsulfonamidovl)-2.6-dichlorobenzoic acid So and Other Compound of Formula 3 Part A: Under an atmosphere of nitrogen gas, a reaction vessel 15 was charged with 2,6-dichlorobenzoic acid (10 g, 53.55 mmol) (Formula F) and chlorosulfonic acid (3 ml, 472 mmol), The reaction mixture was refluxed for 1 hour and cooled to 100C. The contents of the reaction vessel were poured slowly into 3 L of ice water. The white solid which precipitated was collected by Sle': 20 filtration and dried in vacuo (10 mm) at 35 0 C for 48 hours to give 3-(chlorosulfonyl)-2,6-dichlorobenzoic acid (Formula G) (9.2 g, 61% yield).
4 Part B: 3-(Chlorosulfonyl)-2,6-dichlorobenzoic acid (1.5 g; 25 5.2 mmol) was dissolved in anhydrous toluene (35 ml) to which was added powdered K2CO3 (1.44 g: 10.4 mmol) and n-butylamine ml, 10.4 mmol). The reaction mixture was stirred at 25 0 C for 12 hours, The solution was diluted slowly with 1 M ethereal HCI and was then stirred for 30 minutes. The solution was filtered and the resulting filtrate was evaporated to dryness to give crude product. Further purification of the material by silica gel chromatography using EtOAc as the eluent provided 3-(Nbutylsulfonamidoyl)-2,6-dichlorobenzoic acid (Formula 3) (1.43 g, 1H NMR (DMSO) 8 8.11 1H), 7.98 and 7.71 (doublets, 1H each), 2.75 2H), 1.55 2H), 1.32 (m 2H), 0.87 3H).
In a similar manner, the following compounds were prepared: EKDN 62040 2,6-Dichloro-3-sulfonamidoylbenzoic acid (1 H NMR (DMSO) 8.11 1H), 7.42 and 7.15 (doublets, 1H each), 7.26 2H) from 3-chlorosulfonyl-2,6-dichlorobenzoic acid and aqueous ammonium hydroxide.
3-(N-Benzylsulfonamidoyi)-2,6-dichlorobenzoic acid (1 H NMR (DMSO) 8 8.70 1H), 7.90 and 7.65 (doublets, 1H each), 7.25 (in, 5H), 4.15 (in, 2H) from 3-chlorosulfonyl-2,6dlchiorobenzoic acid and benzyl amine.
3 2 -Am in oace t am Ido ]s ulIf on am id oIy) -2,6 dichlorobenzoic acid from 3 -c hlIor os u Ifo ny1- 216 dichlorobenzoic acid and glycinamide (in. p. 210-213 0
C.
Examole 37 3-(N-Morpholino)sulfonamidoyi)-2,6-dichlorobenzoic acid from 3-chlorosuifonyl-2,6-dlchlorobenzoic acid and morpholine.
N-Benzyloxycarbonyl-L-Aspartlc Acid 2.6-Dichiloroggyzovoxvmethyl Ketone-and Other Comlounds, f Formula -1 A solution of f-tert-butyl ester of N-benzyloxycarbonyl-Laspartic acid 2,6-dichlorobenzoyloxymethyl ketone (Example 2) in methylene chloride containing 25% v/v trifluoroacetic acid ml) was stirred for 2 hours at 0CC, The solvent was removed In vacuc and the residue azeotroped three times with methylene chloride to give analytically pure N-benzyloxycarbonyl-L-aspartic -31- EKDN 62040 acid 2,6-dichlorobenzoyloxymethyl ketone (high resolution mass spectrum for CNI0H17CO207 found 453,1572), In a similar fashion, the following compounds of Formulas 1 and 2 were prepared, ExamPI a2 N-Benzyloxycarbonyl-L-aspartic acid 2,6dlfluorophenoxymethyl ketone (high resolution mass spectrum for 0 19 H1 7 F2N06 found 393.3562) from the 3 :6'..tert-butyl ester of Example 3, 15 Exgmpuil 4Q N-Benzyloxycarbonyl-i4-aspartic acid 2,6-ditrifluoromethyl benzoyloxymethyl ketong (high resolution mass spectrum for C22H-17O7Fe, found 521.1452) from the f-tert-butyl ester of Example 4, N-Benzyloxycarbonyl-L-aspartic acid 26 .:dlchlorophenoxymet-yl ketone (mass spectrum m/z 426 from the P-tert-butyl ester of Example Example A2 N-Benzyloxycarbonyl-L-aspartic acid 2-flunro-4-(Nmorpholinyl sulfonamido)phenoxymethyl ketone (rn.p, 66 0 C) from the P-tert-butyl ester of Example 6.
-32- EKDN 62040 N-Benzyloxycarbonyl-L-aspartic acid 2-chloro-4-(Nthiomorpholinyl-sulfonn~mido)phenoxymethyI ketone (mp.
180-181 0 0) from the J-tert-butyl ester of Example 7.
Example -4 N-Benzyloxycarbonyl-L-aspartlc acid 2,6-dichloro-3-(2-Nmorpholinylethoxy)benzoyioxymethyl ketone (high resolution mass spectrum for 026H290 9 N2CI2 found 583.1245 from the P-tert-butyi ester of Example 8, N-Benzyloxycarbonyl-L-aspartic acid 2,6dimethoxybenzoyloxy methyl ketone (high resolution mass spectrum for C 22
H
2 4O9N found 446,1430 )from the f3-tertbutyl ester of Example 9.
N -B en zylIo xy ca rb on yI- L -a s parti1c acid 2,6-dichloro-3- 25(benzyloxy) benzoyloxymethyl ketone (high resolution mass spectrum for 027H-2408NC1 2 found 560,0865 from the P3tert-butyl ester of Example N-Benzyloxycarbonyl-L-aspartic acid 2-acetamido-6chloro-benzoyloxymethyl ketonie (high resolution mass spectrum for C22H220BN2012 found 477,1044) from tche j.
tert-butyl ester of Example 11, .33- -3-EKIDN 62040 g~mple 4Q N-Benzyloxycarbonyl-L-aspartic acid 2,6difluorobenzoyloxymethyl k~etone (high resolution mass spectrum for C2oHIBO7NF2 found 422,1046) from the tert-butyl ester of Example 12.
N-Benzyloxycarbonyl-L-aspartio) acid 3(N *butylsulfonamido)-2,6-dichlorobenzoyloxymethyI ketone 48-5000) from the 1-tert-butyl ester of Example 13.
see* N-Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3sulfonamido benzoyloxymethyl ketone (mp. 44-46 0 C) from the P-tert-butyl ester of Example 14.
N- Be nzy loxycarbo nyI- L-as pa rtic Ac Id 3(N benzylsulfonamido)-2,6-dlchlorobenzoyloxymethyl ketone 66-6811C) from the p3-ert-butyl ester of Exampie EXOMPI!-6 N-Benzyloxycarbonyl-L-aspartlc acid 3(-2 a m 1no ac e tam Id oylI] s u I n a m id 0) -2 6 dichlorobenzoyloxymnethyl ketone 54-56,T) from the p tert-butyl ester of Example 16.
-34- EKDN G2040 N-Benzyloxycarbcryvl-L-aspartic acid 2,6-dichloro-3-(Nrorpholinyl-sulfonamido)benzoyloxymethyl ketone (hi-gh resolution mass spectrum for 0 24
H
2 5 0 1 N2C12 fOUnO .03.0594) from the P-tert-butyl ester of Example 17.
ExaM olR -64 N-Methoxycarb nyl-L-alanine-L-aspa.tlc acid 2,6dichlorobenzoyloxy- methyl ketone Pnal, caic. for C1718O8C2N2 0, 45,45; H, 4.04; N, 6.24. Found: C, 45.20; H, 4.06; N, 5.98) from the P-tert-butyl ester of Example 18.
Exa% ple KI -(2-thi nyl)carbonyI-L-aspart acid 2,6dilctorobenzoyloxymethyl ketone (miss spectrum DL& 430 from the P-tert-butyl ester of Example 19, N-Methoxycarbonyl-glycine-L-aspartic acid 2,6 dichlorbenzoyloxy-methyl ketcne (Anal. caic, for C16H16080,12N2: C, 44.10; H, 3,1'7; N, 6.44. Found: C, 44.24: H, 3.15; N, 6.12 from the Atert-butyl eoier of Example N-Mothoxycarbonyl-L-phanylalanne-L-aspartic acid 2,6dichloro-bLvfnzoyloxymethyl ketone (Anal. calc. for
C
23 H2aO'cIl 2 N2: C, 5259; H, 4.22; N, 5.33, Found: C, 52.98; H, 4.38: N, 5.21) from the P-tert-butyl ester of Example 21.
I
EKDN 62040 Example 58 N-Methoxycarbonyl-L-P-(2-thienyl)aianine-L-aspartic acid 2,6-d i-chlorobenzoyloxymethyl ketone (mass spectrum rnLz 5_U, from the P-tert-butyl ester of Example 22.
N Met h o x yca rb o n y I L-v a 1i n e L- a s p a rt i c acid 2,6dichlorobenzoyloxy-methyl ketone 119-120 0 C) from the P-tert-butyl ester of Example 23.
N-Methoxycarbonyl-L-hstdine-L-aspartic acid 2,6dichlorobenzoyl-oxymethyl ketone (Anal. calo, for
C
22
H
21 0oF 3 Cl 2
N
4 C, 41.99; H, 3.36; N, 8.90, Found: C, 42.08; H, 3.48; N, 8.67; mass spectrum m/z 515 from the 3-tert-butyl ester of Example 24.
Example 61 i N-Benzyloxycarbonyl-L-valine-L-aspartic acid 2,6dichlorobenzoyloxy-methyl ketone (Anal. calc, for 25 C 2 5H 26 0 8 C1 2
N
2 C, 54,26; H, 4,47; N, 5.06. Found: C, 54.06; H, S14.74; N, 4.91) from the -tert-5utyl ester of Example Example 02 N-Benzyloxycarbonyl-L-alanlne-L-aspartic acid 2,6dichlorobe nzoyl-oxymethyl ketone (mass spectrum mLL 525 from the 3-tert-butyl ester of Example 26.
Exampnlg 6.3~ N-Benzyloxycarbonyl-L-valine-L-aianine-L-aspartic acid 2,6-di-chlorobenzoyloxymethyl ketone (Anal. calc. for r~ll -36- EKON 62040 C28H310 9 C12N3: 0, 53.85; H, 5.00; N, 6.73. Found: C, 54.00; H, 5.04; N, 6.66) from the f-tert-butyl ester of Example 27.
N-(2-Furonyl)carbonyl-L-aspartic acid 2,6dichlorobenzoyloxymethyl ketone (mass spectrum m~z. 414 from the 0-tert-butyl ester of Example 28.
aoe6 N-(2-Furonyl)carbonyl-L-aspartic acid 2,6-dichloro-3-(Nmorpholinyl- sulfonamk,,io)be-nzoyloxymethyl ketone (mass spectrum nmL& 563 from the 0-tert-butyl ester of 15 Example 29.
N- 3- P hen yIp ro p o n yI L -a s p a r tc acid 2,6dichlorobenzoyloxymethyl ketone 1 H NMR (CDCI3) 5 7.40 (in, 9H), 5.05 (2xdd, 4H), 4,70 (mn, 1 2.85 (mn, 2.65 (dd, 1H), 2.60 (dd, 2.50 from the P-tert-butyl ester of Example N- Meth oxyca rbo n yI- L -as p artic acid 2,6d Ichlo robe nzoyloxym ethyl ketone (11H NMVR (DMSO) 8 7.6 0 (in, 5.24 (in, 4.51 (in, 1IH), 3.58 3H), 2.75 (dd, I H), 2.55 (dd, 11-) from the 1-tert-butyl ester of Example 31.
N, N-dimethy lainoinethyl) benzoyl-L-aspartic acid 2,6-dichloro-benzoyloxyinethyl ketone 55-5700) from the 1-tert-butyl ester of Example 32.
-37- EKDN 62040 Exmule 69 N-Benzyloxycarbonyl-D-aspartic acid 2,6 dictiiorobenzoyloxymethyI ketone (high resolution mass spectrum for C 2
OH-
1 7C1 2 NO7, found 453.1583) from Nbenzyloxycarbonyl-D-aspartic acid-f3-tert-butyl ester and 2,6-dichlorobenzoic acid using the procedures described in Examples 1, 2 and 38.
Exaple 7 SN-(2-[2,6-dich lo robe nzoyloxy)acetyl-L-aspartic acid 2,6- :**see dich lo robe nzoyloxyrnethyl 'Ketone (mass spectrum m/z 551 from N-Benzyloxycarbonyl-L-aspartic acid 2,6off* 00. 1 d ichlIorobe nzyloxymethylI ketone and 2-(2,6- Oe00 dichlorobenzoyloxy) acetic acid using the procedures described in Examples 18 and 38.
Benzyloxycarbonyl-L-aspartic acid bromomethyl ketone 25 tert-butyl ester, N-benzyloxycarbonyl-L-valine and 4-(N,Ndiethylsulfonamido)-2,3,5,6-tetrafluorophenol using the procedures described in Examples 2, 18 and 38. The 4-(N,Ndiethyl-2,3,5,6-tetrafluorophenol was prepared by reacting 2,3,5,6-tetrafluorophenol with chiorosulfonic acid followed by reaction with diethylamine, analogous to the procedure described in Scheme 11l, and Example 33.
Compounds of the present invention were tested for IL-I p protease inhibition activity according to the following protocol: Partially purified IL-1f3 protease is stored at -80 0 C, thawed on ice, and preincubated for 10 minutes at 370C with 2.5 mM -38- EKDN 62040 dithiothreitol in a buffer solution containing 10 mM Tris-HCI (pH 8.0) and 25% glycerol. Inhibitors are prepared as stock solutions in dimethyl sulfoxide (DMSO). The protease is preincubated with inhibitor in a volume of 20 pl in a ml polypropylene microcentrifuge tube for 15 minutes at 370C. The volume of compound added to the assay is adjusted to yield a DMSO concentration in the preincubation of <15% The enzyme assay is then initiated by the addition of substrate (TRITC-AYVHDAPVRS-NH2) to yield a final concentration of 67 gIM in a final volume of 30 L. The reaction are carried out for 60 minutes at 370C in the dark and are terminated by the addition of 10 p1l of 0' trifluoroacetic acid (TFA). Following the addition of 115 .l 0: of 0.1% TFA, the samples are analyzed by high pressure liquid chromatography using a reverse phase (C18) column and elution with an acetonitrile/water/TFA gradient.
Substrate and product are monitored by their absorbance at 550 nm and elute at 4.2 and 5.2 minutes, respectively.
TABLE I **o *Example No. Name of Compound rluJ-m 25 38 N-Benzyloxycarbonyl-L-aspartic acid 0.05 2,6-dichlorobenzoyloxymethyl ketone N-Benzyloxycarbonyl-L-aspartic acid 0.10 2,6-ditrifluoromethylbenzoyloxymethyl ketone 41 N-Benzyloxycarbonyl-L-aspartic acid 0.10 2,6-dichlorophenoxyrnethyl ketone 42 N-Benzyloxycarbonyl-L-aspartic acid 0.32 2 fluoro 4-(N-morpholinyl sulfonamido)phenoxymethyl ketone 49 N-Benzyloxycarbonyl-L-aspartic acid 0.09 butylsulfonamido)-2,6-dichlorobenzoyloxymethyl ketone c -39- -39- EKDN 62040 TABLE 11(contd.) 52 N-Benzyloxycarbonyl-L-aspartic acid 3- 0.06 (N-(2-ami noacetamidoyljsu Ifonamido)- 2,6-dlch lo robe nzoyl oxymethylI ketone 53 N-Benzyloxycarbonyl-L-aspartic acid 0.09 2,6-dichloro-3-(N-morpholinylsulfonamido)benzoyloxymethyl ketone 54 N- Methoxycarbonyl- L-alIan ine- L-aspartic acid 0.06 2,6-dichlorobenzoyloxymethyl ketone V6004 6499*5 N-Methoxycarbonyl-L-phenylalanine-L-aspartic 0.07 0*060, acid 2,6-d ich lo robe nzoy loxymethyl ketone 64 N-(2-furonyl)carbonyl-L-aspartic acid 2, 6- 0.14 dlichlorobenzoyloxymethyt ketone 67 N-Methoxycarbonyl-L-aspartic acid 0.08 2,6-dichlorobenzoyloxymethyl ketone 68 N-d imethy lam inomethyl) benzoyl-L-aspartic 0.3 acid 2, 6-dlchlorobenzoyloxymethyl ketone N-(2-[2,6-dichlorobenzoyloxyj)acetyl-L-aspartic acid 2,6- 0.2 d ichlo robe nzoyloxymethyl ketone

Claims (12)

1. A compound of the formula (1) H Formula I wherein n 0-4; 0 0* 0* *0 0 0 000 0 0* 0 0000 0**0 *0 0 0 0 H H R 2 R 4 CH 2 0(CO)mRs 0 or H4 PCH 2 (CO)mR 3 OH 0 0 *0 00 0* m 0,1; R3 a singularly or multiply substituted aryl wherein aryl Is a phenyl or naphthyl ring wherein the substituents are independently selected from the group consisting of: H halogen CH CF 3 N02 CORg NR 6 CORio CONRSR36 S02NRSR6 (11 SO2RG (12) COORii -41. -1-EKIDN 62040 (13) -O-(0H 2 16 and (14) lower alkyl and lower cycloalkyl Rs lower straight chain or branched alkyl, lower cycloalkyl (CRBR 7 )'o.6-aryl (CR 6 R7)0. 6 -heteroaryl or (CR6R 7 )2.6-R8; 10 R6 and R7 are independently H, lower straight chain or :branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined :**Sooas above and heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, Imidazolyl, pyrazolyl, isoxazolyl, benzlmidazolyl, pyrazinyt, pyrimidyl, quinolyl, isoquinolyl, isothiazolyl, benzofuranyl, 4 c~Ttriazinyl and tetrazolyl; R 8 OCH2CH, 2 OR 6 OCH2CH:aNR6R 7 NR6CH2C0 2 R6 2 R N x X and NR6R7 wherein R6 and R7 are as above defined; Rg lower straight chain or branched alkyl, lower cycloalkyl (CR6R7)o.6-aryl; (CR 6 R7)0. 6 -heteroary, or (CR6R7)0.6-R8, wherein R6, R7 and R8 are as above defined; Rio R9 EKIDN 62040 0R 1 NR6Rii,1 wherein Rjj cycloalkyl defined; lower straight chain or branched alkyl, lower (CR 6 R7)1-6-aryl; (CRoR7)1-6-heteroaryl; or (CR6R7)2. 6 -R8, and R6, R7 and R8 are as above 4 4* S. S 0tS 9 SSSS S 4 0S** 4 0* *5 S R4 H or deuterium; R 2 (1) (2) (3) OR 6 NR 6 OR7 or NR 6 R37, and R6 and R7 are as above-defined; A an amino acid of the formula (11) R6 Q R 1 2 Formula (11) wherein R6 and R 7 are as defined above; 5 5* S S 5* R12 is independently H or (CR 6 R7)l.6-R13, and R 6 and R 7 are as above- defined;, R13= (1) (2) (3) (4) (6) (7) H F CF3 0R 1 1 NR 6 R14 cycloalkyl EKDN 62040 aryl heteroaryl SH (11 SRii1 (12) CONR5R 6 (13) COOR5 or (14) R R14=- R7 *6@S CORjo S02NR5Rd or *see Nfl 6 ANRr 6 R 7 or *AA an amino acid selected from the group consisting of 0 H NN a H N N f N EKIDN 62040 1 (8) '0 N and (11) (12) *9 S 99 .9 .9 *9 9 9 9* OS*S .5.9 S 69 S 9 .99. Ri is an acyl group of the formula (1ll) N R 2 k Formula III wherein R12 IS 95
9. 9 59 5* 9 9 0* 99 NR,5R 6 R0- ()RSR6N-(CH 2 1 4 -0 EKDN 62040 2 ,R 1 6 CN: wherein R15 single bond, (CH 2 6 -NR6-, (CH 2 2 6 and and RG) are as above defined; or a suifonyl group of the formula (IV) 0 0 Formula IV .e 0 0* 00 0 0 *0 00*0 0 *000 *000 *0 0 0 0000 10 wherein R 16 IS (1 R N R 5 RN-(CH 2 1 4 and R6 are as above-defined. I 00 0 0 *0 00 0 00 wherein Rs 2. A compound according to claim 1 selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6- dlchlorobenzoyloxy-methyl ketone, N-Benzyloxycarbonyl-L- aspartic acid 2,6-difluorophenoxymethyl ketone, N- Benzyloxycarbonyl-L-aspartlc acid 216- ditrlfluoromethylbenzoyloxymethyI ketone, N- Benzyloxycarbonyl-L-aspartic acid 216- dichlorophenoxymethyl ketone and N-Benzyloxycarbony-L- -46. -46- EKDN 62040 aspartic acid 2-f Iuoro-4- (N-morpho I!nylsuIf on arnido)phenoxymethyl ketone. 3. A compound according to claim 1 selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2- chloro-4-(N-thlomorpholinylsuifonamido)phenoxymethyI ketone, N-Benzyloxy,,carbonyl-L-aspartlc acid 2,6-dichioro- 3-(2-N-morphoiinylethoxy) benzyioxymethyl ketone, N- Benzyloxycarbonyl-L-aspartic acid 2,6- dlimethoxybenzoyloxy methyl ketone, N-Benzyloxycarbonyl- L-aspartic acid 2,6-dichloro-3-(benzyioxy)benzyloxymethyl *ketone and N-rBenzylo-^ycarbonyl-eL-aspa-rtic acid 2- acetamnid o-6-chlIo robe nzoyoxy- methyl ketone, 15 4, A compound according to claim 1 selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartlc acid 2,6- dif Iuo robe nzoyloxy- methyl ketone, N-Benzyloxycarbonyl-L- aspartic acid 3-(N-butylsulfonamido)-2,8- dlchlorobenzoyloxymethyi ketone, N-Benzyloxycarbonyl-L- aspartlc acid 2,6-dichloro-3-sulfonamldo benzoylmethyi ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N- benzylsuIf onami do)-2,6-dich lo robe nzoyloxymethyl ketone off$ and N-Benzyloxycarbonyi-L-aspartic acid am In oa ce ta m Ido y I su Ifo na m Id o-2 ,6 25 dichlorobenzoyloxymethyi ketone. A compound according to claim I selected from the group consisting of: N-Benzyloxycarbonyl-L-aspartic acid 2,6- dichioro-3-(N-morpholinylsulfonamldo)benzoyloxymethyI ketone, N-Methoxycarbonyi-L-alanine-L-aspartic acid 2,6- dlchlorobenzoyloxy-methyl ketone, N-(2-thienyl) carbonyl- L-aspartic acid 2,6..dichlorobenzoyloxy-methyl ketone, N- Methoxycarbonyl-glycfne-L-aspartlc acid 2,6- dichlorobenzoyloxymothyl ketone and N-Methoxycarbonyl-L- phenylaianine-L-asparttc acid 2,6-dichloro- benzoyloxymethyl ketone. -47- EKDN 62040 6. A compound according to claim 1 selected from the group consisting of: N-Methoxycarbonyl--P-(2-thienyl)alanine- L-aspartic acid 2,6-di-chlorobenzoyloxymethyl ketone, N- Methoxycarbonyl-L-valine-L-aspartic acid 2,6- dichiorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L- histidlne-L-a~partic acid 2,6-dichlorobenzoyloxy- methyl ketone, N-Benzyloxycarbonyl-L-valine-L-aspartic acid 2,6- dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl- L-alarine-L-aspartic acid 2,6-dlch lo robe nzoyloxymethyl ketone, a7. A compound according to claim 1 selected from the group consisting of: N-Benzyloxycarbonyl-L-valine-L-alanine-L- aspartic acid 2,6-di-chlorobenzoyloxymethyl ketone, N-(2- dIch lo robe nzoyloxymethyl ketone, N-(2-furonyl)oarbonyl-L- aspartic acid 2,6-dlchloro-3-(N-morpholinyisulfonamldo)- benzoyloxymethyl ketone, N-(3-phenyipropionyl)-L-aspatLic acid 2,6-dlchiorobenzoyioxymethyl ketone, N- Metho xycarbo n yl-L-a spa rtle a ci1d 2,6- d Ichlo rob enzoyloxymetlh yl ketone, dimethylamino- ne t hy1) b en z oyI- L -a sp a rt Ic acid 2,6- *dichloro-benzoyloxymt 1'yl ketone, N-benzyloxycarbonyl-D- aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2- 25 dichlorobenzoyloxy])acetyl-L-aspartic acid 2,6- ~dichlorobenzoyioxymethyl ketone and N-Benzyloxycarbonyl- L-vallne-L-aspartlc acid ~cpr~e~==~ei#4-(NN-diethyl-sulfonamldo)-2,3,5,6- tetraflIuo ro-phen oxyrrnethyl ketone. 8. A ph ar mace uti~aI.coposto f btiginj!Zeukin ip protease comp~islng, corpnd of the formi'ia (1) -48- -8-EKIDN 62040 H R A Formula I wherein n -L z Y 0 H 0k H Hh82<UTA CH 2 O(O o or R41k. yCH2(CQ)mR3 U H. see* *06m M 0,1; R3- a singularly or multiply substituted aryl wherein aryl is a phanyI or naphthyl ring wherein the substituents are independently selected from the group consisting of: (1H 406 15 halogen I CH~ C173 N02 ORS COR 9 NR6CORco CONRSRO S0 2 NRsR6 (11 S0 2 R6 (12) COQRII (13) .O.(CHI) 1 .e 1~0 and (14) lower alkyl and lower cycloalkyl -49- -49- EKDN 62040 lower straight chain or branched alkyl, lower cycloalkyl (CRGR7)o-6-aryl (CR6R7)o. 6 -heteroaryl or (CR6R7) 2 .6-R8; R6 and R7 are independently H, lower straight chain or branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined as above and heteroaryl Includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoqulnolyl, isothiazolyl, toobenzofuranyl, ,triazinyl and tetrazolyl; R8 OH 2 CH 2 OR 6 (2)OCH 2 CHA 2 NR 6 R 7 see* NR 6 CH 2 CO 2 R 6 soN x X -0 S and 0:4 20 NR6R7 wherein R 6 and R7 are as above defined; too* R9 lower straight chain or branched alkyl, lower cycloalkyl (CR6R7)o.6-aryl; (CR6R7)o.6-heteroaryl; or (CR 6 R 7 )o. 6 -RB, wherein R 6 R 7 and RB are as above defined; R% R9 ORii1 NR6R1 1, wherein R11 lower straight chain or branched alkyl, lower cycloalkyl EKON 62040 *9 0* p. (CR 6 R 7 1 6 -aryl; (CR6R7)1-s-heteroaryl; or (CR 6 R 7 2 6 -R 8 and R6, R7 and R8 are as above defined; R4 H or deuterium; R 2 OR NR6OR7 or NR6R 7 and R6 and R7 are as above-defined; A ()an amino acid of the formula (11) R 7 R 12 Formula (it) wherein R6 and R 7 are as defined above; R12 is independently H or (CR6R 7 )1.6-RI3, and R6 and R7 are as above- so. 0 goe. 1. so defined; R1 3 H F CF3 CH ORI 1 NR 6 Rj4 cycloalkyl aryl heteroaryl SH (11) SR 1 1 (12) CONR5R6 -51- -51- EKDN 62040 (13) COOR5 or (14) R 1 4 R7 CORjo SO2NR5R6 or Nfl 8 ic orNR 6 R7 A an amino acid selected from the group consisting of 0 0 H0 (4) N >N N j 0 H 0 N HN N .52- -52- EKDN 62040 (8) H H 4N '0 (12)/ (10A and N '0 0 S.O. R 1 is an acyl group of the formula (111) 0 Formula IIl wherein R12 is ORs NR5R6 IRS -CH=CHR R0 S S *5 S. S SS S* R 5 R 6 N.(CH 2 14 R6 rf-_N Ni -53- EKIDN 62040 r0,Rls wherein R15 single bond, (0H 2 2 e-NR 6 (CH 2 and and R 6 are as above defined; or a sulfonyl group of the formula (IV) 0 0 Formula IV 0* *0 *0*0 *00* 0*00 0*0* lo wherein R1 6 is Rs I R 5 R 6 N-(CH 2 1 4 I and R 6 are as above-defined. 00 00 00 0 0* wherein R5 9. The pharmaceutical composition of claim 8 wherein said compound is selected from the group consisting of: N- Benzyloxycarbonyl-L-aspartic acid 2,6-dichlorobenzoyloxy- methyl ketone, N-Benzyloxycarbonyl-L-aspartic ac,-d 2,6- difluorophenoxymethyl ketone, N-Benzyloxycarbonyl-L- aspartic acid 2,6-ditriflIuo rom ethyl benzoyloxymethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 2,6- dichiorophenoxymethyl ketone and N-Benzyloxycarbonyl-L- I .54- EKDN 62040 a s p a r tic a c id 2- flIu o r o (N morpholinylsulfonamido)phenoxymethyl ketone. The pharmaceutical composition of claim 8 wherein said compound is selected from the group consisting of: N- Benzyloxycarbonyl-L-aspartic acid 2-chloro-4-(N- thiomorpholinyl-sulfonamido)phenoxy-methyl ketone, N- Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(2-N- morpholinylethoxy)benzyloxymethyl ketone, N- Benzyloxycarbonyl-L-aspartic acid 2,6- dimethoxybenzoyloxy methyl ketone, N-Benzyloxycarbonyl- L-aspartic acid 2,6-dichloro-3-(benzyloxy)- ease benzyloxymethyl ketone and N-Benzyloxycarbonyl-L- aspartic acid 2-acetamido-6-chlorobenzoyloxymethyl fe. 1 ketone.
11. The pharmaceutical composition of claim 8 wherein said compound is selected from the group consisting of: N- B en zy Io xy ca r b o nyI-L -a sp ar t Ic acid 2,6- 20 difluorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L- aspartic acid 3-(N-butylsulfonamido)-2,6- dichlorobenzoyloxymethyl ketone, N-Benzyloxycarbonyl-L- aspartic acid 2,6-dichloro-3-sulfonamido benzoylmethyl ketone, N-Benzyloxycarbonyl-L-aspartic acid 3-(N- ease,. 25 benzylsulfonamldo)-2,6-dichlorobenzoyloxymethyI ketone and N -B enzy Io x yc ar bo n y I-L-a sp a rt ic acid dichlorobenzoyloxymethyl ketone,
12. The pharmaceutical composition of claim 8 wherein said compound Is selected from the group consisting of: N- Benzyloxycarbonyl-L-aspartic acid 2,6-dichloro-3-(N- morpholinylsulfonamido) benzoyloxymethyl ketone, N- Methoxycarbonyl-L-alanine-L-aspartlc acid 2,6- dichlorobenzoyloxy-methyl ketone, N-(2-thienyl) carbonyl- L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N- EKDN 62040 M ethoxycarbonyl-g lyci ne-L-aspartic acid 2,6- dichlorobenzoyloxy-methyl ketone and N-Methoxycarbonyl- L-phenylalanlne-L-aspartic acid 2,6-dichioro- benzoyloxymethyl ketone.
13. The pharmaceutical composition of claim 8 wherein said compound is selected from the group consisting of: N- Methoxycarbonyl.* L-f-(2-thienyl)alanine-L-aspartic acid 2,6-di-chlorobenzoytloxymethyl ketone, N-Methoxycarbonyl- L-vallne-L-aspartic. acid 2,6-d ich lo robe nzoyl oxy met hyl ketone, N-Methoxycarbonyl-L-histidine-L-aspartic acid 2,6- :dichlorobenzoyloxymethy! ketone, N-Benzyloxycarbonyl-L- valine-L-aspartic acid 2,6-dichlorobenzoylo-Ay-mewthyl ketone and N-Benzyloxycarbonyl-L-,alanine-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, see*
14. The pharmaceutical composition of claim 8 wherein said compound is selected from the group consisting of: N- Benzyloxycarbonyl-L-valine-L-alanine-L-aspartic acid 2,6- 20~ d i-ch lo robe nzoyloxy methyl ketone, N-(2-furonyl)carbonyl- L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N- (2-furonyl)carbonyl-L-aspartic acid 2,6-dichloro-3-(N- morpholinylsulfonamido)- benzoyloxymethyl ketone, N-(3- p henyl propiony I) -L-aspartic acid 2,6- d ich lorobe nzoyloxym ethyl ketone, N-Methoxycarbonyl-L- :aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-(4- (N,N-dimethylamlno- methyl)benzoyl-L-aspartic acid 2,6- d ichloro-be nzoyloxy methyl ketone, N-benzyloxycarbonyl-D- aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2- [2,6-dichlorobenzoyloxy])acetyl-L-aspartic acid 2,6- dichlorobenzoyloxy-methyl ketone and N- Benizyloxycarbonyt-L-valine-L-aspartic acid 4-(N,N- diet hy s ulIfo namid o)-2,395, 6- tetrafIu o ro phenox ym ethy I ketone. -56- r-KDN 62040 A method of inhibiting interleukin-13 protease activity in a mammal in need of such treatment comprising administering to said mammal an effective "Qh ibito ry., amount of a pharmaceutical' compostioW corpslng&\a' compound of the formula or a pharmaceutically acceptable salt thereof A Formula I 9@ 44 9* S 4. S S lo wherein n 0-4; H 12-L'R 2 :CO)MR 3 *CH 2 0(CO6mR 3 iS S S S* S *S m 0,1;" R3 a singularly or multiply substituted aryl wherein aryl Is a phenyl or naphthyl ring wherein the substituents are independently selected from the group consisting of: H halogen CH CF 3 N0 2 OR CQRq NR 6 COF110 CONRsR6 SOpNR5R 6 .57- -57- EKDN 62040 (11) S0 2 R6 (12) OORii1 (13) 4,-(CH 2 16 ~-and 'N OR,, (1 4) lower alkyl and lower cycloalkyl lower straight chain or branched alkyl, lower cycloalkyl (CR6R7)o.6-aryl (CR6R7)o.6-heteroaryl or (CR6R7) 2 R8; R6 and R7 are independently H, lower straight chain or branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined as above and heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, isothiazolyl, 4100x*0.triazinyl and tetrazolyl; IRS- OCH 2 CH2OR6 6:00 OCH 2 CH 2 NR6R7 NR6CH200 2 R6 H 8 N xor-an NR6R7 wherein R6 and R7 are as above defined; R9 lower straight chain or branched alkyl, lower cycloalkyl (CR6R7)o..o-aryl,, (CR6R7)o.6-heteroaryl; or (CR6R7)0.6-R8, wherein R6, R7 and RB are as above Z- 'C _58- -58- EKD'01 ~2040 defined; R 10 R9 ORIi1 NR6RI1I, w herein n h d ak l lo e R1-(1 lower straight chain or branhdakl oe cycloalkyl (CRrOR7)1-6-aryl; (CR6R 7 )1-6-heteroaryl; or (CRGR7)2.6-R8, and R6, R7 and RB are as above defined; R 4 H or deuterium; R 2 ORB 0*00 NR6OR7 or NR6R7, and R6 and R 7 are as above-defined; 066 A ()an amino acid of the formula (11) R~6 0 R 7 R 1 .1 Formula wherein R6 and R7 are as defined arove; R12 is indepenC~ntly H or (CR6R7)1.6-R13, and R 6 and R7 are as above- defined; R13= H F CF 3 C-H EKDN 62040 QR 1 1 NR6RI4 cycloalkyl aryl heteroaryl SH (11) SR11 (12) CONRsR6 (13) COOR5 or (14) *Opj a. a. R14- R7 CORio SO2NRqR6 or NR 6 ANR 8 R7 o r A an amino acid selected from the group 20 consisting of g* 1 EKDN 62040 N 9 060 (8) N N and (12) (11) S. *0 SS 5* S* Ri Is an acyl group of the formula (111) 0 Formula III wherein R12 IS (1 Rs NR 5 R 6 Rs -CH-CH~r, -61- S RSR6N- (C H 2 14 EKDN 62040 S. S S S 40 S S S S 0 *5 S C O I wherein R 1 5 single bond, (CH2)2.6-NR6-, (01-102.6-0- and ard R6 are as above defined; or a sulfonyl group of thet formula (IV) 0 0 Formula IV 00 S wherein R16 Is Rs (2)3 RRN(H). and 8 6 are as above-defined. wherein Rs -62- -62- EKDN 62040
16. The method of claim 15 wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L- aspartic acid 2,6-dichlorobenzoyloxy-methyi ketone, N- Benzyloxycarbonyl-L-aspartic a c id 2,6- difluorophenoxymethyl ketone, N-Benzyloxycarbonyl-L- aspartic acid 2,6-ditrifluoromethyl benzoyloxymethyl ketone, i~-Benzyloxycarbonyl-L-aspartic acid 2,6- enoxymethyl ketone and N ,Benzyloxycuarbonyl-L- a0 as p ar 1c a c Id 2 -f Iu or o -4 morpholinylsulfonamido)phenoxymethyl ketone.
17. The method of claim 15 wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L- aspartic acid 2-chloro-4-(N-thiomorpholinyl- sulfonamldo)phenoxymethyl ketone, N-Benzyloxycarbonyl-L- aspartic a c Id 2 6-dIch lo ro-3-(2-N morpholinylethoxy)benzylo>.ymethyl ketone, acid 2,6- to 0 20dimethoxybenzoyloxy methyl ketone, N-Benzyloxycarbonyl- L-aspartic acid 2,6-dichloro-3-(benzyloxy)bonzyloxymethy #fee ketone and N-Benzyloxycarbonyl-L-aspartic acid 2- acetamido-6-chlorobenzoyloxymethyl ketone.
18. The method of claim 15 wherein said compound is selected from the group consisting of: N-Benzyioxycarbonyi,.L- aspartic acid 2,6-dlfluorobenzoyloxymethyl ketone, N- Benzyloxycarbonyl-L-aspartlc acid 3-(N-butylsulfo~iamIdo)- 2,6-d ich lo robe nzoyloxy methylI ketone, N- Benzyloxycarbonyl-L-aspartlc acid 2,6-dichloro-3- sulfonamido benzoyimethyl ketone, N-Benzyloxycarbonyl-L- aspartic acid 3-(N-benzylsuIf o nam ldo)-2,6- dichlorobenzoyloxymrethyi ketone and N-Benzyl'oycarbonyi- L-aspartic acid 3-(N-[2-aminoacetamidoyl] sulforiar,,ido)- 2,6-clichlorobenzoyloxymethyl ketone, .63- -63- EKDN 62040
19. The method of claim 15 wherein said compound is selected from the group consisting of: N-Benzyloxycarbonyl-L- aspartic acid 2,6-dichloro-3-(N-morpholinysulfonamido) benzoyloxymethyl ketone, N-Methoxycarbonyl-L-alanine-L- aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-(2- thienyl) carbonyl-L-aspartic acid 2,6-dichlorobenzoyloxy- methyl ketone, N-Methoxycarbonyl-glycine-L-aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone and N- Methoxycarbonyl-L-phenyialanine L-aspartic acid 2,6- dichloro-benzoyioxymethyl ketone, The method of claim 15 wherein said compcund is selected from the group consisting of: N-Methoxycarbonyl-L-J3-(2- thie ny1) aIa nin e a s parti1c acid 2, 6 -d I- chlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L- ~valine-L-aspartic acid 2, 6 -d1c hlIo rob e nzo y Io x y-m e thylI ketone, N-Methoxy-.arbonyl-L-histidine-L-aspartic acid 2,6- dichlorobenzoyloxy- methyl ketone, N-Benzyloxycarbonyl-L- ':.vallne-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone and N-Benzyloxycarbonyl-L-alanine-L -aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone.
21. The method of claim 15 wherein said compound Is selected from the group consisting of: N-Benzyloxycarbonyl-L- va 11n e -L-aIa ni1n e- L- a sp art!c acid 2, 6-d I- *ch lo robe nzoy lo xymethyl ketone, N-(2-furonyl)carbonyl-L- aspartic acid 2,6-dichlorobenzoyloxymethyl ketone, N-(2- furonyl)carbonyl-L-aspartic acid 2,6-dichloro-3-(N- rnurph all nylsulf onamido) benzoyloxymethyl ketone, N-(3- phenylpropionyl)-L-aspartic acid 2,6- dichlorobenzoyloxymethyl ketone, N-Methoxycarbonyl-L- aspartic acid 2,6-dichlorobenzoyloxy-methyl ketone, N-(4- (N,N-dimethylanhino- methyl)benzoyl-L-aspartic acid 2,6- dichloro-benzoyloxymethyl ketone, N-benzyloxycarbonyl-D- aspartic acid 2,6-dichlorobenzoyloxymethyI ketone, N-(2- [41,,6-dichlorobenzoyloxyJ)acetyl-L-aspartic acid 2,6- 64 dichlorobenzoyloxy-methyl ketone and N-Benzyloxycarbonyl-L-valine-L-aspartic acid 4-(NN-diethyl-sulfonamido)-2,3, 5,6-tetrafluorophenoxymethyl ketone, 22, A compound according to claim I substantially as hereinbefore described with reference to any one of the examples,
23. A method according to claim 15 substantially as hereinbefore described with reference to any one of the examples. DATED: 13 January 1997 PHILLIPS ORMONDE FITZPATRICK Attorneys for: STERLING WINTHROP INC. S S S S S 5* S S 5. S 55 S S S S S C WNRDxtUMP6CMeo6O52 94 DC EKDN 62040 AUIBACT Disclosed are compounds, compositions and methods for inhibiting interleukin-1f3 protease activity, the compounds having tho formula (1) A n Formula I wherein n 0-4; Y=1 H H R4 CH 2 0(CO)mR 3 o r R4 0CH. 2 (CO)MR 3 U OH R3 a singularly or multiply substituted aryl wherein aryl is a phenyl or naphthyl ring wherein the substituents are independently selected from the group consisting of: H halogen 01 0F3 N02 COR9 NR600Rio CONRsR6 SQ 2 NRsR 6 (11) S02R6 (12) COOR11 -66- EKDN 62040 (13) -O-(CH 2 16 abnd cl' OR 1 1 (14) lower alkyl and lower cycloalkyl R. 5 lower straight chain or branched alkyl, lower cycloalkyl (CR6R7)0-6-aryl (CR6R7)o.6-heteroaryl or (CR6R7)2.6-R8; R 6 and R7 are independently Hl, lower straight chain or branched alkyl, benzyl, aryl, cycloalkyl and aryl is defined :,eta* above and heteroaryl includes pyridyl, thienyl, furyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, benzimidazolyl, *pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, isothiazolyl, benzofuranyl, isoxazolyl, triazinyl and tetrazolyl; R8 OCH 2 CH 2 OR 6 QCH2CH 2 NR 6 R 7 NR 6 CH2CO 2 R6 N H 6 r-\ x X -O,S and NR 6 R7 wherein R 6 and R7 are as above defined; R- lower straight chain or branched alkyl, lower cycloalkyl (CR6R7)o.6-aryl; (CR6R7)o.6-heteroaryl; or (CR6R7)O.6-RB, wherein R 6 R7 and R8 are as above defined; EKDN 62040 R1i (1) (2) (3) wherein Ri1 (1) cycloalkyl (2) (3) (4) OR1i NR6Ri i, lower straight chain or branched alkyl, lower (CR6R 7 )1 -6-aryl; (CR6R7)1-6-heteroaryl; or (CR6R 7 2 .6-R8, and R 6 R7 and R8 are as above C. C 9* C. C C C. C C defined; R4= H or deuterium; R 2 OR 6 15 NR6OR7 or NR6R7, and R6 and R7 are as above-defined; A an amino acid of the formula (11) R6 Q R 7 R 12 Formula 2 wherein R 6 and R 7 are as defined above; R12 is independently H or (CRGR7)1.6-R13, and R6 and R 7 are as above- defined; R 1 3 H F CF73 NR 6 R14 -68- -68- EKDN 62040 cycloalkyl aryl heteroaryl SH (11 SRIi1 (12) CONR5R6 (13) COORS or (14) O-ORII 0 0 00 R14s- (1) (2) (3) R7 S0 2 NRSR6 or NRr ANR 8 R; A an amino acid selected from the group consisting of N 0 0* H 0 H N (7) -69- EKDN 62040 Y (11) KH (10)1 *4i1 N& and (12) 0* 4* S Ri is an acyl group of the formula (111) Formula IIl where in R12 IS (1 OR NR5R6 0* S. S S 55 R 5 0- S6NCH1 -4 EKDN 62040 0 j wherein R15 single bond, (CH 2 2 6 -NR 6 (CH2)2.6-O- and IRS and R6 are as above defined; or a sulfonyl group of the formula (IV) 0 11 S :Formula IV l o wherein R 1 6 is or RSR 6 N-(CH 2 1 4 t wherein R5 and R 6 are as above-defined.
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